The aims of this project are (1) to understand the molecular basis of the diverse pharmacology of estrogens, including the selective estrogen receptor modulators (SERMs) and antiestrogens, (2) to develop novel inhibitors of estrogen action that act by blocking receptor-coactivator interactions, and (3) to prepare protein microarrays that can be used to study how ligands regulate nuclear receptor-coregulator interactions on a genome-wide basis. We will apply advanced fluorescence methodologies to study the conformational dynamics and interactions of the estrogen receptors ERa and ERI3 and their interactions with coregulator proteins and how these are modulated by various ER ligands, including the ER subtype-selective ligands we have developed. Specific studies will focus on the role of protein conformational dynamics and reciprocity in these interactions, competition in recruitment of coactivators vs. corepressors, the agonism of SERMs such as tamoxifen, and ligand regulation of the function of ERc_.ERI3 heterodimers. Using structure-based and de novo design, we will develop small molecule coactivator binding inhibitors that should block estrogen action at a different level than antiestrogens and might overcome antiestrogen resistance in breast cancer. Protein microarrays of nuclear hormone receptors or coregulators will be developed to assay ligand regulation of receptor-coregulator interaction in a rapid, high throughput, genome-wide manner. This project should lead to improved understanding of the molecular basis of estrogen action, novel agents to regulate estrogen activity, and powerful tools for the discovery of novel estrogens and other ligands for nuclear receptors. PERFORMANCESlTE(S)(organ_ation, d_,state) The Board of Trustees of the University of Illinois c/o Grants and Contracts Office 109 Coble Hall 801 South Wright Street Champaign, IL 61820-6242 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Katzenellenbogen, JohnA. University of Illinois Carlson, Kathryn E. University of Illinois Collins, Margaret University of Illinois Daniels, Jonathan University of Illinois Kim, Sung-Hoon University of Illinois Lee, In-Young University of Illinois Rodriguez, Alice Universityof Illinois Tamrazi, Anobel University of Illinois Baudry, Jerome Universityof Illinois Huang, Ziwei University of Illinois Katzenellenbogen, Benita S. University of Illinois Selvin, Paul R. University of Illinois Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. [] Yes [] No PHS 398 (Rev. 05/01) Page 2 information in the format shown below. Role on Project Principal Investigator Research Asst. Graduate Res. Asst. Graduate Res. Asst. Postdoctoral Postdoctoral Graduate Res. Asst. Graduate Res. Asst. Consultant Consultant Consultant Consultant Form Page 2 Principal Investigator/Program Director (Last, first, middle): Katzenellenbo.qen, John A. The name of the principal investigatorlprogram director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page ......................................................................................................................................................... 1 Description,